Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt

ABSTRACT

An extended release pellet comprising an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least one release-modifying excipient.

RELATED APPLICATIONS

This application claims priority to European Application No. 04019249.4filed Aug. 13, 2004, which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention is directed to an extended release pelletformulation containing pramipexole or a pharmaceutically acceptable saltthereof, method for manufacturing the same and use thereof.

BACKGROUND OF THE INVENTION

Pramipexole is a known dopamine D2 receptor agonist. It is structurallydifferent from the ergot-derived drugs, e.g., bromocriptine orpergolide. It is also pharmacologically unique in that it is a fullagonist and has receptor selectivity for the dopamine D2 family ofdopamine receptors.

Pramipexole is designated chemically as(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and has themolecular formula C₁₀H₁₇N₃S and a relative molecular mass of 211.33. Thechemical formula is as follows:

The salt form commonly used is pramipexole dihydrochloride monohydrate(molecular formula C₁₀H₁₂Cl₂N₃OS; relative molecular mass 302.27).Pramipexole dihydrochloride monohydrate is a white to off-white,tasteless, crystalline powder. Melting occurs in the range of 296° C. to301° C., with decomposition. Pramipexole is a chiral compound with onechiral center. Pure (S)-enantiomer is obtained from the syntheticprocess by chiral recrystallization of one of the intermediates duringsynthesis.

Pramipexole dihydrochloride monohydrate is a highly soluble compound.Water solubility is more than 20 mg/mL and solubility in buffer media isgenerally above 10 mg/mL between pH 2 and pH 7.4. Pramipexoledihydrochloride monohydrate is not hygroscopic, and has a highlycrystalline nature. Under milling, the crystal modification(monohydrate) does not change. Pramipexole is very stable in the solidstate, yet in solution it is light sensitive.

Pramipexole immediate release (IR) tablets were first authorized in theUSA in 1997, followed over the course of the next years by marketingauthorizations in the European Union (EU), Switzerland, Canada, andSouth America as well as in countries in Eastern Europe, the Near East,and Asia.

Pramipexole IR tablets are indicated in the EU and US for the treatmentof signs and symptoms of either early Parkinson's Disease or advancedParkinson's Disease in combination with levodopa. The IR tablets have tobe taken 3 times a day.

From the pharmacokinetic point of view, pramipexole IR tablets arerapidly and completely absorbed following oral administration. Theabsolute bioavailability is greater than 90% and the maximum plasmaconcentration occurs within 1 to 3 hours. The rate of absorption isreduced by food intake but not the overall extent of absorption.Pramipexole shows linear kinetics and a relatively small inter-patientvariation of plasma levels. The elimination half-life (t_(1/2)[h])varies from 8 hours in the young to 12 hours in the elderly.

As is commonly known, modified release of active ingredient(s) allowssimplification of the patient's administration scheme by reducing theamount of recommended daily intakes, improves patient's compliance, andattenuates adverse events, e.g., related to high plasma peaks. Modifiedrelease pharmaceutical preparations regulate the release of theincorporated active ingredient or ingredients over time and compriseformulations with a controlled, a prolonged, a sustained, a delayed, aslow or an extended release, so they accomplish therapeutic orconvenience objectives not offered by conventional dosage forms such assolutions or promptly dissolving dosage forms.

A modified or extended release of active ingredient(s) from apharmaceutical preparation may be accomplished by homogeneouslyembedding the active ingredient(s) in a hydrophilic matrix, being asoluble, partially soluble or insoluble network of viscous, hydrophilicpolymers, held together by physical or chemical entanglements, by ionicor crystalline interactions, by complex formation, by hydrogen bonds orvan der Waals forces. The hydrophilic matrix swells upon contact withwater, thereby creating a protective gel layer from which the activeingredient(s) are slowly, gradually, continuously released in timeeither by diffusion through the polymeric network, by erosion of the gellayer, by dissolution of the polymer, or by a combination of theserelease mechanisms.

However, it has proved difficult to formulate a dosage form having asuitable combination of modified, extended, or sustained-release andhandling properties, where the drug is one having relatively highsolubility, as in the case of pramipexole dihydrochloride.

There are a number of approaches described in prior art to providecontrolled release pharmaceutical compositions of pramipexole.

WO 2004/010997 describes a sustained-release pharmaceutical compositionin a form of an orally deliverable tablet comprising a water-solublesalt of pramipexole, dispersed in a matrix comprising a hydrophilicpolymer and a starch having a tensile strength of at least about 0.15 kNcm⁻², preferably at least about 0.175 kN cm⁻², and more preferably atleast about 0.2 kN cm⁻², at a solid fraction representative of thetablet. The disclosure thereof is concentrated to provide a compositionwith sufficient hardness yield during a high-speed tabletting operation,in particular to resist erosion during application of a coating layer.According to a preferred embodiment it is provided a pharmaceuticalcomposition in a form of an orally deliverable tablet having a corecomprising pramipexole dihydrochloride monohydrate in an amount of about0.375, 0.75, 1.5, 3, or 4.5 mg, dispersed in a matrix comprising (a)HPMC type 2208 in an amount of about 35% to about 50% by weight of thetablet and (b) a pregclatinized starch having a tensile strength of atleast about 0.15 kN cm⁻² at a solid fraction of 0.8, in an amount ofabout 45% to about 65% by weight of the tablet; said core beingsubstantially enclosed in a coating that constitutes about 2% to about7% of the weight of the tablet, said coating comprising an ethylcellulose-based hydrophobic or water-insoluble component and anHPMC-based pore-forming component in an amount of about 10% to about 40%by weight of the ethyl cellulose-based component.

Furthermore, WO 2004/010999 discloses an orally deliverablepharmaceutical composition comprising a therapeutically effective amountof pramipexole or a pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient, said compositionexhibiting at least one of (a) an in vitro release profile wherein onaverage no more than about 20% of the pramipexole is dissolved within 2hours after placement of the composition in a standard dissolution test;and (b) an in vivo pramipexole absorption profile following single doseoral administration to healthy adult humans wherein the time to reach amean of 20% absorption is greater than about 2 hours and/or the time toreach a mean of 40% absorption is greater than about 4 hours. However,in practical use, it appears that any formulation having a modified orcontrolled release profile designed for a once daily application wouldmeet the above requirements for which a general teaching how to adjustsuch a profile is missing. All examples are directed to tablets and notto coated pellets.

Absorption profile in vivo with matrix systems is frequently highlyvariable due to differences in gastrointestinal transit times.Multiparticle extended release formulations such as pellets distributein the gastrointestinal tract and therefore show reduced variability inrate and extent of absorption. Furthermore different dose strengths canbe achieved easily by filling different amounts of the same extendedrelease pellet type into capsules. As reproducible absorption ismandatory with pramipexole and there is a wide range of therapeutic dosestrengths, these properties offer considerable advantages of pramipexoleextended release pellets over the predescribed examples mentioned above.

Therefore, it is an object of the present invention to provide anextended release pellet formulation of pramipexole or a pharmaceuticallyacceptable salt thereof which may be filled in a capsule and is suitablefor once-daily oral administration. It is a further object to provide apellet formulation comprising pramipexole or a pharmaceuticallyacceptable salt thereof which may be filled in a capsule and is suitableto provide a day-long therapeutic effect and will allow patients totreat their symptoms with a single daily dose, and makes it possible toadjust the release profile of the active ingredient according to aselected release profile dependent or independent from the pH1 value.Furthermore, a method of manufacturing the pellet formulation shall beprovided.

DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that pramipexole or a pharmaceuticallyacceptable salt thereof may be used in formulations as once dailyextended (or slow) release pellets and two alternative formulationprinciples allow different release rate types dependent or independentfrom the pH value.

One embodiment of the present invention relates to an extended releasepellet comprising an active ingredient selected from pramipexole and thepharmaceutically acceptable salts thereof, and at least onerelease-modifying excipient.

Preferably the invention relates to an extended release pellet, whereinthe active ingredient is embedded within a matrix formed by the at leastone release-modifying excipient, which is preferably selected from thegroup of lipids, waxes, and water-insoluble polymers.

Also preferred is an extended release pellet comprising a core and acoating, wherein at least one release-modifying excipient isincorporated in the coating.

Also preferred is an extended release pellet, wherein the activeingredient is incorporated in the core.

Also preferred is an extended release pellet, wherein the coatingcomprises at least a first layer and a second layer surrounding thefirst layer, wherein the first layer comprises the active ingredient,and wherein the second layer comprises at least one release-modifyingexcipient, preferably selected from ethyl cellulose, cellulose acetate,polyvinylacetate, polyacrylates, polymethacrylates, and ammoniomethacrylate copolymer.

Most preferred is an extended release pellet, wherein the second layerfurther comprises at least one water-soluble excipient, preferablyselected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyvinylpyrrolidone, and polyethylene glycol.

Particularly preferred is an extended release pellet, wherein the secondlayer further comprises an enteric-coating polymer, preferably selectedfrom methacrylic acid copolymers type A and B.

Particularly preferred is an extended release pellet, wherein the secondlayer comprises from about 10 to about 85 wt.-% of the enteric-coatingpolymer and from about 15 to about 75 wt.-% of the water-insolublepolymer.

More particularly preferred is an extended release pellet, wherein thecore comprises a saccharide, such as saccharose, starch, cellulose, anda cellulose derivative, preferably microcrystalline cellulose.

In a further embodiment the present invention relates to an extendedrelease pellet formulation comprising:

-   -   an inert pellet core;    -   a first layer being an active ingredient layer comprising        pramipexole or a pharmaceutically acceptable salt thereof and        optionally one or more wet binders and other excipients; and    -   a second layer provided on the first layer, the second layer        being an extended release coating comprising:        -   (a) at least one water-insoluble polymer and optionally a            pore former, the resulting pellet having a pH-independent in            vitro release characteristic, or        -   (b) a mixture of a pH-dependent enteric-coating polymer and            a pH-independently water swelling polymer, the resulting            pellet having a close to zero order in vitro release            characteristic at acidic pH values up to pH 6.8, an            accelerated release above pH 6.8 and a more accelerated            release above pH 7.3.

The expression “layer” should be understood in its broadest sense alsoincluding a coating or a film or any kind of (partly or fully)surrounding material used in the pharmaceutical sector and having adefined thickness.

Instead of using an inert pellet core and a first layer of activeprinciple, pellets can also be formed by extrusion of active principletogether with excipients in a wet extrusion or melt extrusion process.

The extended release formulations (a) and (b) according to the presentinvention intended for oral administration allow to select and estimatewhich in vitro release characteristic and timing of a formulation ismost suitable to achieve the desired in vivo plasma profiles preferablywith a once daily application. Therefore, two different formulationprinciples have been developed for pellets. The two formulationprinciples have different release rate types and a different pHdependency is available. These alternative formulations are beneficialto patients as the extended release drug delivery will allow patients totreat their symptoms with a single daily dose, thereby increasingpatient convenience and compliance.

The term “in vitro release characteristic” as used hereinbefore orhereinafter is directed to a release characteristic as obtained in akind of normally used liquid medium for in vitro experiments wherein therelease of active ingredient from the extended release formulation canoccur, i.e., for example, in in vitro dissolution media, but also inbody fluids or simulated body fluids, more in particular in thegastrointestinal fluids.

In the frame of the present invention the term “extended” release shouldbe understood in contrast to an immediate release, the active ingredientis gradually, continuously liberated over time, sometimes slower orfaster, dependent or independent from the pH value. In particular, theterm indicates that the formulation does not release the full dose ofthe active ingredient immediately after oral dosing and that theformulation allows a reduction in dosage frequency, following thedefinition for extended release, interchangeable with slow release. Aslow or extended release dosage form is used synonymously with prolongedaction, sustained release, or modified release dosage form. Preferablythe extended release dosage form allows at least a two-fold reduction indosing frequency or a significant increase in patient compliance ortherapeutic performance as compared to that presented as a conventionaldosage form (e.g., as a solution or a prompt drug-releasing,conventional solid dosage form).

According to the teaching of the present invention two types of extendedrelease pellet formulations are available showing different in vitrorelease characteristics. The two types have the same structure, i.e., aninert pellet core and a first and a second layer applied thereon in thisorder, the first layer represents the active ingredient layer comprisingpramipexole or a pharmaceutically acceptable salt thereof and optionallya binder and further excipients, the second layer represents afunctional coating either comprising a water-insoluble polymer with apore former or a mixture of an enteric-coating polymer, i.e., which isresistant against gastric juice, and a nondissolving water swellingpolymer.

According to the present invention under “formulation (a)” is understoodthe pellet formulation having the second layer as above-defined under(a) and under “formulation (b)” is understood the pellet formulationhaving the second layer as above-defined under (b) whereas the inertpellet core and first layer compositions of formulation (a) and (b) willbe the same.

The extended release pellet formulation (a) of the present inventionapplies a water-insoluble polymer preferably with a pore former in thesecond layer leading to an exponential (1^(st) order) in vitro releasecharacteristic, which is widely independent of the pH value. Theextended release pellet formulation (b) of the present invention appliesa mixture of a pH-dependent enteric-coating polymer and apH-independently water swelling polymer, the resulting layer having aclose to zero order in vitro release characteristic over a broad periodof time at acidic pH values up to pH 6.8, an accelerated release abovepH 6.8 and an more accelerated release above pH 7.3. In addition to theclose to zero order release for the main portion of drug, the latter isfurthermore characterized by a certain lag time until drug releasebecomes substantial and, after the main portion of drug is released, bya flattening of the release profile until an asymptote is reached. Thisresults in a sigmoid profile, i.e., an S-shaped dissolution profile.

A close to zero order in vitro release characteristic indicates a curvewhich has a virtually constant ascending slope.

The inert pellet core present in both alternate pellet formulations (a)and (b) of the present invention comprises saccharides, preferablypolysaccharides, cellulose or a cellulose derivative, starch, and/orwaxes. It is preferred if the core consists of or essentially consistsof a saccharide, preferably polysaccharide, or cellulose, particularlypreferred saccharose or microcrystalline cellulose. Most preferred ismicrocrystalline cellulose. The size of the cores may be sieve fractionsbetween 0.1 and 3.0 mm, preferably between 0.5 and 1.5 mm.

In case the inert pellet core consists or essentially consists ofmicrocrystalline cellulose it has been found that the thickness of thesecond layer applied thereon may be decreased to a great extent comparedto the use of other core materials, e.g., if the core is composed ofsaccharose. Therefore, the amount of release controlling polymericagents and overall spray volumes as well as process times to apply thecoating dispersions or solutions may be reduced significantly while therelease profile for the active ingredient may be maintained. The relatedadvantages are reducing the amount of excipient and solvent materialsused, reducing the process times and the embodiment is cost-saving.

The expression “consisting essentially” is understood in the sense thatit does not in principle exclude the presence, in addition to themandatory components mentioned, of other components, the latter can beexcipients, the presence of which does not affect the essential natureof the formulation.

According to pellet formulations (a) and (b) of the present inventionthere is provided a first layer or coating on the inert core pelletcomprising pramipexole or a pharmaceutically acceptable salt thereof andoptionally one or more binders and further excipients. The first layeror coating normally has a thickness of 0.5 to 25 μm, preferably 1 to 5μm.

As active ingredient pramipexole or a pharmaceutically acceptable saltthereof may be present in any amount suitable for the desired treatmentof a patient. A preferred salt of pramipexole is the dihydrochloridesalt, most preferably in the form of the monohydrate. Usual amounts arefrom about 0.1 to about 5 mg pramipexole salt. According to a preferredembodiment, e.g., 0.750 mg pramipexole dihydrochloride monohydrate,corresponding to 0.524 mg anhydrous base, is used in the extendedrelease capsule or tablet formulation according to the present inventiontaking into account that all pellets which are filled in a capsule orcompressed into a tablet are to give the desired dose strengths.Preferably the extended release pellets are filled into hard capsules,but also compressing of the pellets together with further excipientsinto tablets is possible.

However, any other amount of active ingredient suitable for treatmentmay be used with the only proviso that the amount of pramipexole orsalt, that is the whole number of pellets being present in one capsule,is sufficient to provide a daily dose in one to a small plurality, forexample one to about 4, of capsules to be administered at one time.Preferably the full daily dose is delivered in a single capsule. Anamount of pramipexole salt, expressed as pramipexole dihydrochloridemonohydrate equivalent, of about 0.1 to about 10 mg per capsule, orabout 0.05% to about 5% by weight of the composition, will generally besuitable. Preferably an amount of about 0.2 to about 6 mg, morepreferably an amount of about 0.3 to about 5 mg, per capsule is present.Specific dosage amounts per capsule, e.g., include 0.375, 0.5, 0.75,1.0, 1.5, 3.0, and 4.5 mg pramipexole dihydrochloride monohydrate. Theamount that constitutes a therapeutically effective amount variesaccording to the condition being treated, the severity of saidcondition, and the patient being treated.

The binder(s) present in the first layer may be any suitable wetbinder(s) as used in the pharmaceutical sector. Examples are hydrophilicpolymers which may swell and glue upon contact with water. The viscosityof the polymers preferably ranges from 1 to 1,000 mPa·s (apparentviscosity of a 2% aqueous solution at 20° C.). Examples of such polymersare alkylcelluloses, such as, methyl cellulose; hydroxyalkylcelluloses,for example, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose and hydroxybutyl cellulose; hydroxyalkylalkylcelluloses, such as, hydroxyethyl methyl cellulose andhydroxypropyl methyl cellulose; carboxyalkylcelluloses, such as,carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses,such as, sodium carboxymethylcellulose; carboxyalkylalkylcelluloses,such as, carboxymethyl ethyl cellulose; carboxyalkylcellulose esters;other natural, semisynthetic, or synthetic polysaccharides, such as,alginic acid, alkali metal and ammonium salts thereof, carrageenans,galactomannans, tragacanth, agar-agar, gum arabicum, guar gum, xanthangum, starches, pectins, such as sodium carboxymethylamylopectin, chitinderivates such as chitosan, polyfructans, inulin; polyacrylic acids andthe salts thereof; polymethacrylic acids and the salts thereof,methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone,copolymers of polyvinylpyrrolidone with vinyl acetate; combinations ofpolyvinyl alcohol and polyvinylpyrrolidone; polyalkylene oxides such aspolyethylene oxide and polypropylene oxide and copolymers of ethyleneoxide and propylene oxide.

Preferable binders are polysaccharides, in particular cellulosederivatives and more preferred cellulose ether derivatives. A mostpreferred cellulose ether derivative is hydroxypropyl cellulose.

Different viscosity grades of hydroxypropyl cellulose and hydroxypropylmethylcellulose are commercially available. Hydroxypropyl methylcellulose preferably used as a wet binder in the present invention has aviscosity grade ranging from about 3 mPa·s to about 1,000 mPa·s, inparticular ranging from about 3 mPa·s to about 20 mPa·s and preferably aviscosity grade of about 4 mPa·s to about 18 mPa·s (apparent viscosityof a 2% aqueous solution at 20° C.), e.g., hypromellose 2910 (DOW,Antwerp, Belgium).

Hydroxypropyl cellulose having a viscosity lower than 1,500 mPa·s(apparent viscosity of 1% aqueous solution at 20° C.) is preferred, inparticular hydroxypropyl cellulose having a viscosity in the range fromabout 75 to about 150 mPa·s (5% aqueous solution), preferably from 300to 600 mPa·s (10% aqueous solution), e.g., KLUCEL® EFO (Hercules,Wilmington, USA).

Preferably, the amount of binder in the first layer of the pelletformulations (a) and (b) of the present invention ranges from 0 to about30% by weight, preferably from about 10 to about 20% by weight. Also, acombination of binders may be used.

According to a preferred embodiment of the present invention the firstlayer of the extended release pellet formulation of alternatives (a) and(b) comprises or consists of hydroxypropyl cellulose, pramipexole or apharmaceutically acceptable salt thereof and excipients. The amount ofhydroxypropyl cellulose is preferably in the range from 1 to 30,particularly preferred from 5 to 25, most preferred from 10 to 20% byweight. The amount of excipients is preferably in the range from 1 to40, particularly preferred from 2 to 25, most preferred from 5 to 15% byweight.

Beside pramipexole or a salt thereof, and the binder(s), the first layeror coating of both formulations (a) and (b) of the present invention mayalso optionally comprise excipients, i.e., pharmaceutically acceptableformulating agents, in order to promote the manufacture and coatingproperties of the preparation. These formulating agents comprise, forexample, glidants, antiadherents, binding agents, granulating agents,anti-caking agents, and lubricants. Other conventional excipients knownin the art can also be included.

A glidant and antiadherent can be used to improve the manufacturingduring the spray process and to prevent sticking and picking of thepellets to each other. Suitable glidants include colloidal silicondioxide, magnesium trisilicate, powdered cellulose, starch, talc,tribasic calcium phosphate and the like. In a preferred embodiment, talcis included as a glidant/antiadherent in an amount up to about 25%,preferably about 5% to about 15%, by weight of the first layer.

According to the present invention waxes, lipids, and water-insolublepolymers may be used as release modifying agents.

Suitable waxes include compounds that are chemically defined as estersof fatty acids and fatty alcohols or sterols, as well as derivatives andfunctional analogues thereof. Usually, the chain length of the fattyacid moiety is at least about 8 carbon atoms, and more typically atleast about 12 carbon atoms. Waxes are plastic solids at roomtemperature, but very often have a moderately low melting point, such asbelow about 80° C.-100° C. Waxes are usually somewhat more brittle thansolid fats, and less greasy. More recently, also compounds which arechemically different from this definition but similar in theirproperties have been referred to as waxes. These waxes or functionalanalogues may also be used according to the present invention. Examplesof potentially suitable waxes and wax analogues include white and yellowbeeswax, carnauba wax, microcrystalline wax, spermaceti wax, candellilawax, saturated fatty acid esters, sugar cane wax, paraffin wax, castorwax, and wax mixtures such as nonionic or anionic emulsifying wax, cetylesters wax, and lanolin. Among the presently preferred waxes arebeeswax, carnauba wax, saturated fatty acid esters, and microcrystallinewax.

Suitable lipids include lipophilic compounds or mixtures of natural orsynthetic origin that have similar properties as glycerides and othernatural lipids, such as phospholipids, sphingolipids, ceramides,sterols, steroids, and carotenoids. Lipids may be solid or liquid atroom temperature, and may be viscous in their liquid state. Preferably,a lipid used to carry out the invention is solid at room temperature,even though a liquid lipid may also be used in mixtures, such as in amixture with a solid lipid or wax. Examples of lipids which may be founduseful include mono-, di-, and glycerides of saturated or unsaturatedfatty acids, such as—optionally hydrated or partially hydrated—vegetableoils (e.g., peanut, castor, coconut, cottonseed, palm, or soybean),edible fat, hard fat, glyceryl behenate, glyceryl stearate, glycerylpalmitate; fatty acids such as stearic acid, behenic acid, palmiticacid, oleic acid, lauric acid, myristic acid, arachidic acid, linolenicacid, linoleic acid, arachidonic acid, and erucic acid; fatty alcoholssuch as those corresponding to the previously mentioned fatty acids, inparticular cetyl alcohol, stearyl alcohol, oleyl alcohol, and palmitylalcohol; glycerides, fatty acids, or fatty alcohols which are modifiedwith sorbitan or polyoxyethylene; and phospholipids such as lecithin orphosphatidylcholine. Particularly suitable lipids are solid or at leastpartially hydrated triglycerides including edible fat, hard fat,hydrated peanut-, castor-, coconut-, cottonseed-, palm-, and soybeanoil, glyceryl behenate, glyceryl stearate, glyceryl palmitate, stearicacid, behenic acid, and palmitic acid.

Suitable water-insoluble polymers may comprise the water-insolublepolymers as defined below for the formulations according to the presentinvention.

Among the optional formulating agents that further may be comprised inthe pellet formulation there may be mentioned agents such as polyvidone;starch; acacia gum; gelatin; seaweed derivatives, e.g., alginic acid,sodium and calcium alginate; cellulose, preferably microcrystallinecellulose, cellulose derivatives, e.g., ethyl cellulose, hydroxypropylmethyl cellulose, having useful binding and granulating properties.

According to the pellet formulation (a) of the present invention thesecond layer is provided on the first layer, the second layer, afunctional layer, being an extended release coating or film coatingcomprising at least one water-insoluble polymer and preferably a poreformer, the resulting pellet having an pH-independent in vitro releasecharacteristic. Therefore, the second layer is a non soluble diffusionlacquer with pores leading to an exponential (1^(st) order) releaseprofile of the pellet formulation (a) which has practically apH-independent in vitro release characteristic. A release characteristicwhich is pH-independent indicates that the release characteristic isvirtually the same in different pH media.

The water-insoluble polymer according to the present invention isdefined as a polymer having a water solubility which is lower than 1part soluble in 1,000, preferably lower than about 1 part soluble in10,000 parts of solvent.

The release-controlling second layer, coating or film according topellet formulation (a) comprises one or more hydrophobic orwater-insoluble polymers such as cellulosic polymers e.g., methylcellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose esterssuch as cellulose acetate, polyvinyl acetate, polymers and copolymers ofacrylic acid and methacrylic acid and esters thereof, such as ammoniomethacrylate copolymer, type B, and the like. Particularly preferred isethyl cellulose.

The hydrophobic or water-insoluble component, preferably ethylcellulose,typically constitutes about 1% to about 25%, preferably about 3% toabout 10%, by weight of the pellet as a whole, provided thatmicrocrystalline cellulose pellets are used as described above. In casesugar pellets are used higher amounts of ethylcellulose can becomenecessary.

The second layer can contain one or more pore formers, such as morewater soluble polymers, like hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and highly water soluble polymers, like polyvinylpyrrolidone and polyethylene glycol, or other water soluble excipients,such as lactose and mannitol. Particularly preferred pore formers arepolyethylene glycols (e.g., Macrogol 6000). The amount of pore former issuitably up to 40 percent by weight of the layer, coating or film,preferably up to 25% by weight. Pore formers like polyethylene glycolsalso serve as plasticizers, i.e., the function of such excipients eitheras plasticizer and/or pore former can not be clearly differentiated.

The second layer can optionally contain additional pharmaceuticallyacceptable excipients as mentioned above, preferably used areplasticizers, dyes and antiadherents. Particularly preferredplasticizers are polyethylene glycols (e.g., Macrogol 6000), triacetin,and triethylcitrate. The amount of plasticizer is suitably up to 25percent by weight of the layer, coating or film. Anti-adherents, such astalc and magnesium stearate can be used.

The extended release pellet formulation according to formulation (a) ispH-independent. Therefore, the disadvantage that food relateddose-dumping which may be encountered is avoided. The problem of foodrelated dose-dumping in fed patients can be attributed to a lot offactors such as the mechanical forces that are exerted by the stomach onits content and thus on an ingested preparation as well as the differentpH regions of the gastrointestinal tract. Since the pH valuesencountered in the gastrointestinal tract vary not only with the regionof the tract, but also with the intake of food, an extended releaseformulation preferably also has to provide a controlled release profileand in particular has to avoid dose-dumping regardless whether thepatient is in fasted or fed conditions.

Therefore, the oral extended release formulation (a) according to thepresent invention retains its pharmacokinetic release profile along itsway through the gastrointestinal tract so as to avoid undesirablefluctuations in drug plasma concentrations or complete dose-dumping, inparticular avoids dose-dumping in different regions of thegastrointestinal tract.

The alternate pellet formulation (b) has the same structure with regardto the inert pellet core and first layer composition as defined forformulation (a) but a different second layer or functional film coatingcomposition. Thus, the second layer of formulation (b) comprises oressentially consists of a mixture of a pH-dependent enteric-coatingpolymer and a pH-independently water swelling polymer, the resultingpellet having a close to zero order in vitro release characteristic atacidic pH values up to pH 6.8, an accelerated release above pH 6.8 and amore accelerated release above pH 7.3.

The pH-dependent enteric-coating polymer is preferably an anionicpolymer, more preferably an anionic carboxylic acrylic polymer solubleabove a pH value of 5.5, preferably above a pH value of 7.0. By ananionic polymer is meant a polymer containing anionic groups afterdissociation depending on pH. For the purpose of this invention suchpolymer should be soluble above pH 5.5, preferably above pH 7.0.Preferably the anionic carboxylic acrylic polymer is selected frompartly methyl esterified methacrylic acid polymers. Suitable partlymethyl esterified methacrylic acid polymers are sold under the namesEUDRAGIT® L and EUDRAGIT® S, preferably used are EUDRAGIT® S1100 andL100.

The water-insoluble, pH-independent swelling polymer is preferablyselected from quaternary ammonium substituted acrylic polymers. Suchpolymers are sold under the names EUDRAGIT® RS and EUDRAGIT® RL havingan ammonium substitution of about 5 and about 10 percent by weight,respectively. Preferably EUDRAGIT® RS 100 is used.

It is especially preferred if the layer or film coating comprises theenteric-coating polymer such as the anionic carboxylic acrylic polymerin an amount of 10 to 85 percent by weight of the layer or coating andthe water-insoluble, pH-independent swelling polymer, selected fromquaternary ammonium substituted acrylic polymers, in an amount of 15 to75 percent by weight of the layer or coating. Depending on the amountand ratio of polymers processed in the preparation, the release profilecan be tuned with regard to the release rate, that is the time to, e.g.,reach a level of 50% of drug dissolved, and with regard to the extent ofpH dependency. In general, an excess of the anionic carboxylic acrylicpolymer, e.g., EUDRAGIT® S 100, over the quaternary ammonium substitutedacrylic polymers is required to achieve the desired accelerateddissolution characteristic at a pH above 6.8,

The second layer, coating or film normally has a thickness of 5 to 80μm, preferably 20 to 60 μm.

The second functional layer according to formulation (b) of the presentinvention takes advantage of the fact that the time of passage throughthe small intestine is rather constant, said time is about 2 to 5 hours.According to the invention the change of pH from acid to about neutralat the pylorus is employed as a trigger mechanism changing the physicalcondition of the layer and finally causing the accelerated release ofthe active substance. Therefore the formulation releases a major part ofits drug contents in the small intestine, and in the lower part of theintestinal system preferentially in the large intestine, i.e., thecolon. With a layer or coating according to formulation (b) the releaseof pramipexole or a pharmaceutically acceptable salt thereof can beaccelerated in the lower parts of the intestine, that is underconditions of higher physiological pH, thereby reducing the loss inbioavailability and increase in variability typically observed with pHindependent release systems in situations of shorter gastrointestinaltransit times

According to a preferred embodiment of the present invention apore-forming component may be present in the second layer or filmcoating of formulation (b). The pore-forming component may be selectedfrom the group consisting of water soluble polymers, such aspolyethylene glycols, polyvinyl pyrrolidone, and cellulose derivatives,such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose,preferably hydroxypropyl cellulose. The pore-forming component istypically present in an amount of about 1% to about 25%, preferablyabout 2% to about 10%, by weight of the polymer mixture in the secondlayer.

A particular preferred pore-forming component is hydroxypropyl cellulosehaving a viscosity in the range from about 150 to about 700 mPa·s,preferably from 200 to 600 mPa·s, e.g., selected from the KLUCEL® seriessuch as KLUCEL® EF or LF (Hercules, Wilmington, USA).

The polymer pore-forming component forms diffusion pores and leads to anaccelerated hydration and an altering of the rebuffering characteristicsof the layer or film coating with a change from acid to alkaline mediumand results in an accelerated penetrability of the layer or coating forthe active ingredient pramipexole or its salt in the pH range >7.3

Therefore, the presence of a pore-forming component provides the furtheradvantage that the release characteristic is accelerated and occurs morerapid, i.e., the effects of the second layer are enhanced significantly.

According to a preferred embodiment an extended release pelletformulation has the following composition:

Inert Pellet Core

90 to 100% by weight of saccharose or microcrystalline cellulose; and 0to 10% by weight of excipient(s)

First Layer

50 to 100% by weight of pramipexole or a salt thereof; 0 to 30% byweight of binder(s); and 0 to 50% by weight of excipient(s)

Second Layer

50 to 99% by weight of water-insoluble polymer(s); and 1 to 50% byweight of excipient(s) or a mixture of:

10 to 85% by weight of a pH-dependent enteric-coating polymer; 15 to 75%by weight of a pH-independently water swelling polymer; and 1 to 50% byweight of excipient(s).

The first and second layers or coatings should be applied at as uniforma thickness as possible to provide optimum control of release rate ofthe pramipexole or pramipexole salt.

If pellets are formed by extrusion, the following compositions are mostsuitable:

Wet Extrusion

Microcrystalline cellulose, powdered cellulose or starch is mixed withpramipexole in ratios delivering the necessary amount of drug in asuitable number of pellets with regard to reproducibility of filling andacceptable capsule size. Extrusion is achieved by addition of water onlyor of water containing binders such as povidone or methyl cellulose,hydroxypropyl cellulose. In order to achieve the desired release rates,other excipients such as lactose, microcrystalline cellulose, starch,etc., can be added.

Melt Extrusion

Melt extrusion is achieved either by hydrophilic or lipophilic compoundswith melting points between 40° C. and 120° C. Suitable examples arepolyethylene glycol 2000-10000, poloxamer 188, carnauba wax,hydrogenated castor oil, stearyl alcohol, cetyl alcohol and mixturesthereof. In order to achieve the desired release rates, other excipientssuch as lactose, microcrystalline cellulose, starch, etc., can be added.

These pellets are then coated by retarding lacquers as described for thepellets consisting of inert starters with drug layers sprayed onto them.

Some excipients are suitable also to achieve extruded pellets withsuitable extended release even without retarding lacquers. These are,e.g., carnauba wax, hydrogenated castor oil and mixtures thereof forlipophilic pellets or carbopol, anionic carboxylic acrylic polymer,e.g., partly methyl esterified methacrylic acid polymers. Suitablepartly methyl esterified methacrylic acid polymers are sold under thenames EUDRAGIT® L and EUDRAGIT® S, preferably used are EUDRAGIT® S100and L100.

The extended release pellets can be of sizes between 0.2 and 3 mm indiameter, preferably between 0.5 to 1.5 mm, most preferred between 0.7and 1.0 mm. According to the present invention the pellets arepreferably filled in hard capsules. The extended release capsules can beof any size and shape and color, e.g., for a 0.75 mg dose strengthspreferably a size 3 capsule can be used. The capsule shell is usuallymade from hydroxypropyl methyl cellulose (so-called HPMC or vegetablecapsules) or gelatin. The capsules according to the present inventionare usually filled with pellets, for example, more than 150 extendedrelease pellets. Each pellet is built up of an inert (starter) corepellet, an active ingredient layer and an extended or slow release filmcoating. In one capsule, the amount of pramipexole or thepharmaceutically acceptable salt thereof contained in the pellets maypreferably be sufficient to provide a daily dose administered at onetime.

Alternatively the extended release pellets can be admixed with fillersand binders, such as microcrystalline cellulose, carrageenans, andalginates and disintegrants, such as sodium starch glycolate, sodiumcarboxymethyl cellulose (croscarmellose), further excipients, likeglidants and lubricants, and be compressed into tablets.

The present invention is further directed to the use of the extendedrelease pellet formulation or capsule according to the present inventionfor preparing a medical composition for the treatment of Parkinson'sDisease and complications or disorders associated therewith.

According to the present invention it is also provided a method ofmanufacturing the extended release pellet formulation comprising thesteps of

-   -   (1) providing an inert starter pellet core;    -   (2) applying a solution or dispersion of a first coating        composition comprising pramipexole or a pharmaceutically        acceptable salt thereof, optionally a binder and further        excipient(s) onto the inert starter pellet core, preferably by        spraying the solution/dispersion of the coating composition onto        the inert starter pellet core, wherein the active ingredient in        form of pramipexole or a pharmaceutically acceptable salt        thereof is used as unmilled or milled material,        dissolved/dispersed in a solvent together with the optional        binder(s) and excipient(s) and sprayed onto the inert starter        pellet core and subsequently drying the obtained active        ingredient pellet; and    -   (3) applying a solution or dispersion of a second coating        composition as functional coating composition onto the active        ingredient pellet obtained in step (2), preferably by spraying        the coating solution/dispersion onto the active ingredient        pellet wherein the coating composition comprises (a) at least        one water-insoluble polymer or (b) a mixture of a pH-dependent        enteric-coating polymer and a pH-independently water swelling        polymer, and optional excipient(s), and a solvent and        subsequently drying the obtained extended release pellet (ER        pellet).

Optionally a manual screening after process step (2) and/or process step(3) may be performed in order to remove agglomerates.

The solvents employed according to the process of the invention aresolvents having a sufficient volatility to evaporate under theconditions of application, leaving a layer of the solute on the surfaceof the core or body or pellet prepared. Organic solvents such asalcohols, hydrocarbons and esters may be used as well as derivativesthereof, such as chlorinated hydrocarbons. Particularly preferred arealcohol such as ethanol or alcohol/water mixtures. The process ofapplying the coating may be carried out in an apparatus normally used inthe pharmaceutical industry for coating of solid pharmaceuticalpreparations, preferably in a fluid bed apparatus. The process isnormally carried out at 25° C. to 35° C. product temperature, however,temperature and pressure conditions may be varied within broad limits.In a fluid bed spraying process, the temperature of the inlet air issuitably about 20° C. to 60° C.

The obtained extended release pellets are filled in suitable capsulesand the capsules of the invention can be packaged in a container,accompanied by a package insert providing pertinent information such as,for example, dosage and administration information, contraindications,precautions, drug interactions and adverse reactions. The capsules arefor example filled into High Density Polyethylene (HDPE) bottles. Thebottles are closed tightly with screw caps and appropriately labeled.All packaging and labeling activities are performed according to cGMPregulations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram illustrating process step (1) of a preferredembodiment of the manufacturing process according to the presentinvention wherein the first layer is applied on inert starter corepellets;

FIG. 2 is a flow diagram illustrating process step (2) of a preferredembodiment of the manufacturing process according to the presentinvention wherein the second layer is applied on the first layer of thepellets;

FIG. 3 is a flow diagram illustrating process step (3) of a preferredembodiment of the manufacturing process according to the presentinvention wherein the pellets are filled in capsules;

FIG. 4 is a graph illustrating the dissolution profiles of a pelletformulation according to the present invention wherein the second layeris a diffusion lacquer composed of ethyl cellulose (formulation (a)) in3 different pH media;

FIG. 5 is a graph illustrating the dissolution profiles of a pelletformulation according to the present invention wherein the second layeris a mixture of EUDRAGIT® S 100 and EUDRAGIT® RS 100 (formulation (b))in 4 different pH media; and

FIG. 6 is a graph illustrating the dissolution profiles of a pelletformulation according to the present invention wherein the second layeris as defined in FIG. 5, but a pore-forming component is additionallypresent (formulation (b)+pore-forming component) in 3 different pHmedia.

Referring to FIGS. 1 and 2 a preferred embodiment of the manufacturingprocess is illustrated with reference to a flow diagram wherein themanufacture of the pellet formulations D, E, F, G, H of Examples 1 to 5is exemplarily shown. The figures show the detailed process steps of themanufacturing process of the active ingredient pellets (first layer;FIG. 1) and of the slow or extended release pellets (second orfunctional layer; FIG. 2) and the in process controls performed. FIG. 3shows the filling of capsules with the obtained pellets.

The manufacturing process described applies to all types of pramipexoleextended release pellets and capsules, for example the formulations D,E, F, G, H of Examples 1 to 5, yet there are differences in thequalitative and quantitative composition in some process steps.

Process Step (1)—Inert Starter Pellet Core:

In the present embodiment microcrystalline cellulose pellets (Cellets700) are used which represent the starting material for the subsequentcoating step.

Process Step (2)—Active Ingredient Pellets (First Coating):

For all types of formulations the same active ingredient pellets with adrug load of 1% (10 mg/g) can serve as starting material for thefunctional film-coating. Yet also other drug loads in the activeingredient pellets are suitable.

According to the present flow chart in FIG. 1, the active ingredientpellets are manufactured by spray-layering of an aqueous solution ofpramipexole dihydrochloride monohydrate (active ingredient), unmilledquality, together with hydroxypropyl cellulose (binder) and talc(excipient) onto the surface of microcrystalline cellulose pellets(core, Cellets 700) in a bottom spray fluid bed equipment. Lightprotection of the spray suspension is normally required. After thespraying is completed, the pellets are dried at 35° C. for 1 hour in atray dryer. After drying, the pellets are manually screened through a1.12 mm mesh size screen in order to remove agglomerates.

The in process controls used are: active ingredient assay and loss ondrying.

Process Step (3)—Functional Film Coating (Second Coating):

Depending on the type of formulation (D-H) coating suspensionsconsisting of methacrylic acid copolymer (type B USP/NF)) and ammoniomethacrylate copolymer (type B USP/NF)), or ethyl cellulose, andexcipients selected from talc, triacetin or triethylcitrate andhydroxypropyl cellulose or macrogol 6000, are sprayed onto the activeingredient pellets in a bottom spray fluid bed equipment. The solventused is according to the described embodiment either Ethanol 96% or anEthanol 96% mixture with water. After the spraying is completed theextended or slow release pellets are dried at 40° C. for 12 to 48 hoursin a tray dryer. After drying, the pellets are manually screened througha 1.12 mm mesh size screen in order to remove agglomerates.

The in process controls used are: active ingredient assay and loss ondrying.

Process Step (4)—Capsule Filling (at the Example of 0.75 mg DoseStrength):

An appropriate amount of dried and screened pellets are filled intovegetable capsules (HPMC capsules) or gelatin capsules of size 3 to givethe desired dose strengths using a suitable intermittent motion capsulefilling machine. The appropriate amount is calculated from the assayresult found for the respective batch of slow or extended releasepellets.

The in process controls used are: average mass of empty capsules, massof filled capsule, and length of closed capsule.

Referring to FIG. 4, it represents a graph illustrating the releaseprofiles of a pellet formulation according to the present invention. Thepellet contains an inert pellet core, a first layer comprisingpramipexole hydrochloride monohydrate and binder and a second layerwhich represents a diffusion lacquer composed of ethyl cellulose. Thedetailed composition of the pellet is given in Example 4. The pelletmeets the requirements as defined in the abovementioned formulation (a)according to the present invention. The release characteristics of thepellet formulation in 3 different pH media are shown, i.e., in simulatedgastric juice, n=3, in 0.05 M phosphate buffer, pH=6.8, n=3 and inacetate buffer, pH=4.5, n=3 (n . . . represents the number of unitstested). The value percent of released active ingredient is plottedagainst the time (hours).

FIG. 4 clearly shows that said pellet formulation has a releasecharacteristic being independent from the pH value.

FIG. 5 represents a graph illustrating the release profiles of a pelletformulation according to the present invention. The detailed compositionof the pellet is given in Example 2. The pellet formulation has a secondlayer in accordance with formulation (b) which is composed of apH-dependent enteric-coating polymer and a pH-independently waterswelling polymer (EUDRAGIT®D S100/EUDRAGIT® RS 100). The releasecharacteristics of the pellet formulation in 4 different pH media areshown, i.e., in acetate buffer, pH=4.5, n=3, in 0.05 M phosphate buffer,pH=7.5, n=2, in 0.05 M phosphate buffer, pH 6.8, n=3, and in simulatedgastric juice, pH=1.3, n=3. The value percent of released activeingredient is plotted against the time (hours).

FIG. 5 clearly shows that the pellet formulation has a releasecharacteristic being dependent from the pH value, i.e., the resultingpellet shows a close to zero order in vitro release characteristic atacidic pH values up to pH 6.8, and an accelerated release at pH 7.5.

FIG. 6 represents a graph illustrating the release profiles of a pelletformulation according to the present invention. The detailed compositionof the pellet is given in Example 5. The pellet formulation has a secondlayer in accordance with formulation (b) which is composed of apH-dependent enteric-coating polymer and a pH-independently waterswelling polymer (EUDRAGIT® S310/EUDRAGIT® RS 100) and containsadditionally a pore-forming component (KLUCEL® EF) and a plasticizer(triethylcitrate). The release characteristics of the pellet formulationin 3 different pH media are shown, i.e., in 0.05 M phosphate buffer,pH=6.8, n=3, in 0.05 M phosphate buffer, pH=6.3, n=3, and in 0.05 Mphosphate buffer, pH=7.3, n 3. The value percent of released activeingredient is plotted against the time (hours).

FIG. 6 clearly shows that the pellet formulation has a releasecharacteristic being dependent from the pH value. The presence of apore-forming component and the use of a different plasticizer increasesand accelerates the effects significantly, compared with the pelletformulation without pore-forming component as shown in FIG. 5.

The advantages of the present invention are manifold:

According to the present invention two types of extended release pelletscontaining pramipexole or a pharmaceutically acceptable salt thereof areavailable showing different in vitro release profiles. The two typeshave the same structure, i.e., an inert starter pellet core and a firstlayer or coating and second layer or functional film coating provided onthe core in this order. The core and first layer or coating areidentical and the second layer or coating allows to tune the releasingcharacteristic as desired.

According to formulation (a) of the present invention at least onewater-insoluble polymer is present in the second layer, the resultingpellet having a pH-independent in vitro release characteristic.

According to formulation (b) of the present invention the second layercomprises a mixture of a pH-dependent enteric-coating polymer and apH-independently water swelling polymer, the resulting pellet having aclose to zero order in vitro release characteristic at acidic pH valuesup to pH 6.8, an accelerated release above pH 6.8 and a more acceleratedrelease above pH 7.3. In the latter case (formulation (b)) theadditional presence of a pore-forming component has the significanteffect that the release characteristic is enhanced and acceleratedcompared with the same formulation without a pore-forming component.

Therefore, with a layer or coating according to formulation (b) theextent of release of pramipexole or a pharmaceutically acceptable saltthereof can become more independent of gastrointestinal transit andhence dwell time of the dosage form in the intestine.

It is therefore possible to select a tailor-made release characteristicfor patient's needs, symptoms and clinical picture observed, a desiredrelease with a reduced inter- and intraindividual variability ofbioavailability.

In case the inert pellet core consists or essentially consists ofmicrocrystalline cellulose, the thickness of the second layer and theamount of release controlling excipients applied thereon may bedecreased to a great extent compared to the use of other core materials,e.g., if the core is composed of saccharose.

The primary indication for pramipexole, Parkinson's Disease, is anaffliction that becomes more prevalent with advancing age and is oftenaccompanied by decline in memory. Therefore, the pellets according tothe present invention providing an extended or slow release ofpramipexole or a salt thereof allows to simplify the patient'sadministration scheme by reducing the amount of recommended dailyintakes and improves patient's compliance, particularly relevant forelderly patients. The inventive extended release pellet formulationsprovide a daily dose administered at one time. The amount thatconstitutes a therapeutically effective amount varies according to thecondition being treated, the severity of said condition, and the patientbeing treated.

It is further provided a manufacturing process which applies to alltypes of pramipexole extended release pellets and capsules.

The invention described will now be illustrated by the Examples whichfollow various other embodiments and will become apparent to the skilledperson from the present specification. However, it is expressly pointedout that the Examples and description are intended solely as anillustration and should not be regarded as restricting the invention.

EXAMPLES

In the following Examples cap and body white opaque hydroxypropyl methylcellulose capsules of size 3 are used, filled with extended releasepellets. The complete capsules are intended to be administered orally,and shall not be opened before use. The pramipexole pellets in theExamples contain 0.75 mg of pramipexole dihydrochloride monohydrate,corresponding to 0.524 mg of pramipexole free, anhydrous base.

Example 1

One embodiment of the qualitative and quantitative composition ofpramipexole extended release pellets according to the present invention(Formulation D) is shown in Table 1.

TABLE 1 Qualitative and Quantitative Composition of Pramipexole ExtendedRelease (ER) Capsule (Formulation D) mg per mg per 0.75 mg 0.75 mgReference to Ingredient capsule capsule Function Standards ER Pelletsconsisting of: 88.458 Pramipexole dihydrochloride 0.750 Activeingredient Company monohydrate standard Microcrystalline cellulosepellets 73.980 Non-pareille carrier Ph.Eur./NF (Cellets 700) pelletHydroxypropyl cellulose 0.150 Wet binder Ph.Eur./NF (KLUCEL ® EF) Talc0.495 Glidant Ph.Eur./USP Methacrylic acid copolymer, 7.500 Functionalcoating Ph.Eur./NF Type B (EUDRAGIT ® S 100) Ammonio methacrylate 3.750Functional coating Ph.Eur./NF copolymer, Type B (EUDRAGIT ® RS 100)Triacetin 1.833 Plasticizer Ph.Eur./USP Ethanol (96%) 173.333* SolventPh.Eur. Purified water 30.000* Solvent Ph.Eur./USP HPMC capsule, size 346.000 Shell Company Standard Total 134.458 88.458 *removed duringprocessing (does not appear in the final product)

Example 2

One embodiment of the qualitative and quantitative composition ofpramipexole extended release pellets according to the present inventionFormulation B) is shown in Table 2.

TABLE 2 Qualitative and Quantitative Composition of Pramipexole ERCapsule (Formulation E) mg per mg per 0.75 mg 0.75 mg Reference toIngredient capsule capsule Function Standards ER Pellets consisting of:91.600 Pramipexole dihydrochloride 0.750 Active ingredient Corporatemonohydrate standard Microcrystalline cellulose pellets 73.980Non-pareille carrier Ph.Eur/NF (Cellets 700) pellet Hydroxypropylcellulose 0.150 Wet binder Ph.Eur./NF (KLUCEL ® EF) Talc 0.578 GlidantPh.Eur./USP Methacrylic acid copolymer, 9.250 Functional coatingPh.Eur./NF Type B (EUDRAGIT ® S 100) Ammonio methacrylate 4.625Functional coating Ph.Eur./NF copolymer, Type B (EUDRAGIT ® RS 100)Triacetin 2.267 Plasticizer Ph.Eur./USP Ethanol (96%) 214.167* SolventPh.Eur. Purified water 30.000* Solvent Ph.Eur./USP HPMC capsule, size 346.000 Shell Company Standard Total 137.600 91.600 *removed duringprocessing (does not appear in the final product)

Example 3

One embodiment of the qualitative and quantitative composition ofpramipexole extended release pellets according to the present invention(Formulation F) is shown in Table 3.

TABLE 3 Qualitative and Quantitative Composition of Pramipexole ERCapsule (Formulation F) mg per mg per 0.75 mg 0.75 mg Reference toIngredient capsule capsule Function Standards ER Pellets consisting of:80.063 Pramipexole dihydrochloride 0.750 Active ingredient Corporatemonohydrate standard Microcrystalline cellulose pellets 73.980Non-pareille carrier Ph.Eur/NF (Cellets 700) pellet Hydroxypropylcellulose 0.150 Wet binder Ph.Eur./NF (KLUCEL ® EF) Talc 0.495 GlidantPh.Eur./USP Ethyl cellulose (N14) 3.750 Functional coating Ph.Eur./NFMacrogol 6000 0.938 Plasticizer Ph.Eur./USP Ethanol (96%) 49.167*Solvent Ph.Eur. Purified water 32.583* Solvent Ph.Eur./USP HPMC capsule,size 3 46.000 Shell Company Standard Total 126.063 80.063 *removedduring processing (does not appear in the final product)

Example 4

One embodiment of the qualitative and quantitative composition ofpramipexole extended release pellets according to the present invention(Formulation G) is shown in Table 4.

TABLE 4 Qualitative and Quantitative Composition of Pramipexole ERCapsule (Formulation G) mg per mg per 0.75 mg 0.75 mg Reference toIngredient capsule capsule Function Standards ER Pellets consisting of:82.088 Pramipexole dihydrochloride 0.750 Active ingredient Corporatemonohydrate standard Microcrystalline cellulose pellets 73.980Non-pareille carrier Ph.Eur/NF (Cellets 700) pellet Hydroxypropylcellulose 0.150 Wet binder Ph.Eur./NF (KLUCEL ® EF) Talc 0.645 GlidantPh.Eur./USP Ethyl cellulose (N14) 5.250 Functional coating Ph.Eur./NFMacrogol 6000 1.313 Plasticizer Ph.Eur./USP Ethanol (96%) 68.333*Solvent Ph.Eur. Purified water 33.667* Solvent Ph.Eur./USP HPMC capsule,size 3 46.000 Shell Company Standard Total 128.088 82.088 *removedduring processing (does not appear in the final product)

Example 5

One embodiment of the qualitative and quantitative composition ofpramipexole extended release pellets according to the present invention(Formulation H) is shown in Table 5.

TABLE 5 Qualitative and Quantitative Composition of Pramipexole ERCapsule (Formulation H) mg per mg per 0.75 mg 0.75 mg Reference toIngredient capsule capsule Function Standards ER Pellets consisting of:93.668 Pramipexole dihydrochloride 0.750 Active ingredient Corporatemonohydrate standard Microcrystalline cellulose 73.980 Non-pareillePh.Eur/NF pellets (Cellets 700) carrier pellet Hydroxypropyl cellulose0.630 Wet binder/pore Ph.Eur./NF (KLUCEL ® EF) former Talc 1.995 GlidantPh.Eur./USP Methacrylic acid copolymer, 9.000 Functional Ph.Eur./NF TypeB (EUDRAGIT ® S 100) coating Ammonio methacrylate 4.500 FunctionalPh.Eur./NF copolymer, Type B coating (EUDRAGIT ® RS 100) Triethylcitrate2.813 Plasticizer Ph.Eur./NF Ethanol (96%) 250.200* Solvent Ph.Eur.Purified water 30.000* Solvent Ph.Eur./USP HPMC capsule, size 3 46.000Shell Company Standard Total 139.668 93.668 *removed during processing(does not appear in the final product)

Example 6

The batch formula for the two pramipexole extended release pelletformulations of Example 1 and 2 (Formulations D and E) is shown in Table6. The batch size for the active ingredient layering is 1 kg, the batchsize for the functional slow release film-coating of the active pelletsis 530.748 g (Formulation D) and 549.600 g (Formulation E),corresponding to a theoretical batch size of 6000 capsules each.

TABLE 6 Composition Per Batch of Pramipexole ER Capsules (Formulation Dand Formulation E) Grams Grams per batch per batch Ingredient(formulation D) (formulation E) Active ingredient layering suspension:Pramipexole dihydrochloride 10.000 10.000 monohydrate Hydroxypropylcellulose 2.000 2.000 Talc 1.600 1.600 Purified water 400.000* 400.000*13.600** 13.600** Active ingredient layering: Active ingredient layeringsuspension 13.600** 13.600** Microcrystalline cellulose pellets 986.400986.400 Active pellets 1000.000 1000.000 ER coating suspension:Methacrylic Acid Copolymer, Type B 45.000 55.500 Ammonio Methacrylate22.500 27.750 Copolymer, Type B Triacetin 10.998 13.602 Talc 2.250 2.748Ethanol (96%) 1039.998* 1285.002* 80.748** 99.600** Functionalfilm-coating: Active pellets 450.000 450.000 ER coating suspension80.748** 99.600** Extended release pellets 530.748 549.600Encapsulation: Extended release pellets 530.748 549.600 Capsule shell276.000 276.000 Total Weight 806.748 825.600 Number of capsules (actualdepending 6000 6000 on assay of pellets and yield) *removed duringprocessing (does not appear in the final product) **dry matter

Example 7

The batch formula for the two pramipexole capsule formulations ofExample 3 and 4 (Formulations F and G) is shown in Table 7. The batchsize for the active ingredient layering is 1 kg, the batch size for thefunctional slow release film-coating of the active pellets is 480.378 g(Formulation F) and 492.528 g (Formulation G), corresponding to atheoretical batch size of 6000 capsules each.

TABLE 7 Composition Per Batch of Pramipexole ER Capsules (Formulation Fand Formulation G) Grams per batch Grams per batch Ingredient(Formulation F) (Formulation G) Active ingredient layering suspension:Pramipexole 10.000 10.000 dihydrochloride monohydrate Hydroxypropylcellulose 2.000 2.000 Talc 1.600 1.600 Purified water 400.000* 400.000*13.600** 13.600** Active ingredient layering: Active ingredient layering13.600** 13.600** suspension Microcrystalline cellulose pellets 986.400986.400 Active pellets 1000.000 1000.000 ER coating suspension: Ethylcellulose (N14) 22.500 31.500 Macrogol 6000 5.628 7.878 Talc 2.250 3.150Purified water 15.498* 22.002* Ethanol (96%) 295.002* 409.998* 30.378**42.528** Functional film-coating: Active pellets 450.000 450.000 ERcoating suspension 30.378** 42.528** Slow release pellets 480.378492.528 Encapsulation: Slow release pellets 480.378 492.528 Capsuleshell 276.000 276.000 Total Weight 756.378 768.528 Number of capsules(actual 6000 6000 depending on assay of pellets and yield) *removedduring processing (does not appear in the final product) **dry matter

Example 8

The batch formula for the pramipexole pellet formulation of Example 5(Formulation H) is shown in Table 8. The batch size for the activeingredient layering is 1 kg, the batch size for the functional slowrelease film-coating of the active pellets is 562.008 g, correspondingto a theoretical batch size of 6000 capsules each.

TABLE 8 Composition Per Batch of Pramipexole ER Capsules (Formulation H)Grams per batch Ingredient (Formulation H) Active ingredient layeringsuspension: Pramipexole dihydrochloride monohydrate 10.000 Hydroxypropylcellulose 2.000 Talc 1.600 Purified water 400.000* 13.600** Activeingredient layering: Active ingredient layering suspension 13.600**Microcrystalline cellulose pellets 986.400 Active pellets 1000.000 ERcoating suspension: Methacrylic Acid Copolymer, Type B 54.000 AmmonioMethacrylate Copolymer, Type B 27.000 Hydroxypropyl cellulose 2.880Triethyl citrate 16.878 Talc 11.250 Ethanol (96%) 1501.200* 112.008**Functional film-coating: Active pellets 450.000 ER coating suspension112.008** Extended release pellets 562.008 Encapsulation: Slow releasepellets 562.008 Capsule shell 276.000 Total Weight 838.008 Number ofcapsules (actual depending 6000 on assay of pellets and yield) *removedduring processing (does not appear in the final product) **dry matter

Example 9 Pellets Prepared by Wet Extrusion

In order to achieve adequate content uniformity, 9 g of microcrystallinecellulose is mixed with 1 g of pramipexole. Then this mixture is mixedwith 90 g of microcrystalline cellulose. The mixture is extruded in atwin screw extruder with an adequate amount of water (or bindersolution), diameter of dye is 0.7 mm. The resulting extrudates arerounded in a spheronizer at 400 rpm. After drying pellets are sieved,the fraction of 0.8-1.1 mm is used for retardation as described in theprevious examples. Table 9 provides some further examples of wetextrusion

TABLE 9 Further Examples for Wet Extrusion Example PramipexoleMicrocrystalline No. [g] cellulose [g] Binder [g]  9 1 69 0  9a 0.5 99.50 99b 2 98 0 99c 1 98 1 (povidone K25) 99d 1 98 1 (hydroxypropylcellulose) 99e 0.5 98.5 1 (methyl cellulose)

Example 10 Pellets Prepared by Melt Extrusion with HydrophilicExcipients

In order to achieve adequate content uniformity, 9 g of polyethyleneglycol 6000 (PEG) is mixed with 1 g of pramipexole. Then this mixture ismixed with 50 g of PEG 6000 and 40 g of poloxamer 188. The mixture isextruded in a twin screw extruder at 54° C., diameter of dye is 0.7 mmusing a face cut granulator to achieve pieces of about 1 mm. These arerounded in a spheronizer at 400 rpm and 41° C. The pellets are sieved,the fraction of 0.8-1.1 mm is used for retardation as described in theprevious examples. Table 10 provides some further examples of meltextrusion

TABLE 10 Examples for Melt Extrusion Example Pramipexole PEG PoloxamerNo. [g] 6000 [g] 188 [g] 10 1 59 40 10a 0.5 59.5 40 10b 2 58 40 10c 0.569 30

Example 11 Pellets Prepared by Melt Extrusion with HydrophobicExcipients

In order to achieve adequate content uniformity, 9 g of stearyl alcoholis mixed with 1 g of pramipexole. Then this mixture is mixed with 90 gof stearyl alcohol. The mixture is extruded in a twin screw extruder at51° C., diameter of dye is 0.7 mm using a face cut granulator to achievepieces of about 1 mm. These are rounded in a spheronizer at 400 rpm and41° C. The pellets are sieved, the fraction of 0.8-1.1 mm is used forretardation as described in the previous examples. Table 11 providessome further examples of melt extrusion.

TABLE 11 Further Examples for Melt Extrusion Example Pramipexole StearylCetyl No. [g] alcohol [g] alcohol [g] 11 1 99 0 10a 0.5 59.5 40 10b 2 5840 10c 0.5 49 50

Example 12 Extended Release Pellets Prepared by Wet Extrusion

In order to achieve adequate content uniformity, 9 g of microcrystallinecellulose is mixed with 1 g of pramipexole. Then this mixture is mixedwith 60 g of microcrystalline cellulose and 30 g of carbomer 971P. Themixture is extruded in a twin screw extruder with an adequate amount ofwater (or binder solution), diameter of dye is 0.7 mm. The resultingextrudates are rounded in a spheronizer at 400 rpm. After drying,pellets are sieved, the fraction of 0.8-1.1 mm is filled into capsules.Table 12 provides some further examples of wet extrusion

TABLE 12 Further Examples for Extended Release Pellets Prepared by WetExtrusion Example Microcrystalline Extended release No. Pramipexole [g]cellulose [g] excipient [g] 12 1 69 30 carbomer 971P 12a 0.5 69.5 30carbomer 971P 12b 2 68 30 carbomer 971P 12c 1 69 30 EUDRAGIT ® S 12d 158 40 EUDRAGIT ® S 12e 1 44 30 EUDRAGIT ® S 25 carbomer 971P

Example 13 Extended Release Pellets Prepared by Melt Extrusion

In order to achieve adequate content uniformity, 9 g of hydrogenatedcastor oil is mixed with 1 g of pramipexole. Then this mixture is mixedwith 60 g of hydrogenated castor oil and 30 g of carnauba wax. Themixture is extruded in a twin screw extruder with an adequate amount ofwater (or binder solution), diameter of dye is 0.7 mm. The resultingextrudates are rounded in a spheronizer at 400 rpm. Pellets are sieved,the fraction of 0.8-1.1 mm is filled into capsules. Table 13 providessome further examples of melt extrusion

TABLE 13 Further Examples for Extended Release Pellets Prepared by MeltExtrusion Example hydrogenated carnauba No. Pramipexole [g] castor oil[g] wax [g] 13 1 69 30 13a 0.5 69.5 30 13b 2 68 30 13c 1 59 40 13d 1 7821 12e 1 83 16

Example 14 Extended Release Pellets Prepared by Hot MeltGranulation/Melt Pelletization

In this process, agglomeration of active ingredient with excipients ispromoted by the addition of low melting point, lipophilic binders, suchas waxes, fats, fatty acids, fatty acid alcohols, and more water solublepolymers, such as poloxamers or polyethylene glycols. The binder isusually added to the other components as a powder. The binder isliquefied by heat generated either by friction during the mixing phaseor by a heating jacket. Excipients suitable are, e.g., lactose,microcrystalline cellulose, and dibasic calcium phosphate. After meltingand granulation of the mass, the resulting mass is either cooled down,screened and processed into tablets together with further excipients or,spheronized into pellets, which can be coated in addition, and filledinto capsules

TABLE 14 Examples for Extended Release Pellets Prepared by Hot MeltGranulation/Melt Pelletization Pramipexole carnauba Example No. [%]Lactose Stearyl alcohol [%] wax [%] 14 0.9 74.1 15 10 14a 1.4 58.6 15 2514b 0.9 79.1 15 5

1. An extended release pellet comprising pramipexole or apharmaceutically acceptable salt thereof, and at least onerelease-modifying excipient.
 2. The extended release pellet according toclaim 1, wherein the pramipexole or the pharmaceutically acceptable saltthereof is embedded within a matrix formed by at least onerelease-modifying excipient.
 3. The extended release pellet according toclaim 1, wherein at least one of the release-modifying excipients is alipid, wax, or water-insoluble polymer.
 4. The extended release pelletaccording to claim 1, comprising a core and a coating, wherein at leastone release-modifying excipient is incorporated in the coating.
 5. Theextended release pellet according to claim 4, wherein the pramipexole orthe pharmaceutically acceptable salt thereof is incorporated in thecore.
 6. The extended release pellet according to claim 4, wherein thecoating comprises at least a first layer and a second layer surroundingthe first layer, wherein the first layer comprises the pramipexole orthe pharmaceutically acceptable salt thereof, and wherein the secondlayer comprises at least one release-modifying excipient.
 7. Theextended release pellet according to claim 6, wherein at least onerelease-modifying excipient is ethyl cellulose, cellulose acetate,polyvinylacetate, polyacrylate, polymethacrylate, or ammoniomethacrylate copolymer.
 8. The extended release pellet according toclaim 7, wherein the second layer further comprises at least onewater-soluble excipient.
 9. The extended release pellet according toclaim 8, wherein at least one water-soluble excipient is hydroxypropylcellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, andpolyethylene glycol.
 10. The extended release pellet according to claim7, wherein the second layer further comprises an enteric coatingpolymer.
 11. The extended release pellet according to claim 8, whereinenteric coating polymer is methacrylic acid copolymers type A and B. 12.The extended release pellet according to claim 10, wherein the secondlayer comprises from about 10 to about 85 wt.-% of the enteric coatingpolymer and from about 15 to about 75 wt.-% of the water-insolublepolymer.
 13. The extended release pellet according to claim 6, whereinthe core comprises a saccharide.
 14. The extended release pelletaccording to claim 13, wherein the saccharide is saccharose, starch,cellulose, or a cellulose derivative.
 15. The extended release pelletaccording to claim 14, wherein the saccharide is microcrystallinecellulose.
 16. An extended release pellet comprising: (1) an inertpellet core; (2) a first layer comprising pramipexole or apharmaceutically acceptable salt thereof; and (3) a second layerprovided on the first layer, the second layer being an extended releasecoating comprising: (a) at least one water-insoluble polymer andoptionally a pore former, the resulting pellet having a pH-independentin vitro release characteristic, or (b) a mixture of a pH-dependententeric-coating polymer and a pH-independently water swelling polymer,wherein the extended release pellet has a close to zero order in vitrorelease characteristic at acidic pH values up to pH 6.8, an acceleratedrelease above pH 6.8, and a more accelerated release above pH 7.3. 17.The extended release pellet according to claim 16, wherein the firstlayer further comprises one or more wet binders and further excipients.18. The extended release pellet according to claim 16, wherein the inertpellet core comprises polysaccharides, cellulose, a cellulosederivative, starch, and/or waxes.
 19. The extended release pelletaccording to claim 16, wherein the inert pellet core comprisessaccharose and/or microcrystalline cellulose.
 20. The extended releasepellet according to claim 16, wherein the water-insoluble polymer isethyl cellulose, cellulose acetate, polyvinylacetate, or polyacrylatesand derivatives thereof.
 21. The extended release pellet according toclaim 16, wherein the pH-dependent enteric-coating polymer is an anioniccarboxylic acrylic polymer soluble above a pH value of 5.5.
 22. Theextended release pellet according to claim 21, wherein the pH-dependententeric-coating polymer is soluble above a pH value of 7.0.
 23. Theextended release pellet according to claim 21, wherein the pH-dependententeric-coating polymer is a partly methyl esterified methacrylic acidpolymer.
 24. The extended release pellet according to claim 16, whereinthe pH-independently water swelling polymer is a quaternary ammoniumsubstituted acrylic polymer.
 25. The extended release pellet accordingto claim 24, wherein the quaternary ammonium substituted acrylic polymerhas an ammonium substitution of about 5 to about 10 percent by weight.26. The extended release pellet according to claim 16, wherein thepH-dependent enteric-coating polymer is present in an amount of 10 to85% by weight of the coating and the pH-independently water swellingpolymer is present in an amount of 15 to 75% by weight of the coating.27. The extended release pellet according to claim 21, wherein thepH-dependent enteric-coating polymer is present in an amount of 10 to85% by weight of the coating and the pH-independently water swellingpolymer is present in an amount of 15 to 75% by weight of the coating.28. The extended release pellet according to claim 24, wherein thepH-dependent enteric-coating polymer is present in an amount of 10 to85% by weight of the coating and the pH-independently water swellingpolymer is present in an amount of 15 to 75% by weight of the coating.29. The extended release pellet according to claim 16, comprising: (1)an inert pellet core; (2) a first layer comprising pramipexole or apharmaceutically acceptable salt thereof; and (3) a second layerprovided on the first layer, the second layer being an extended releasecoating comprising a mixture of: (i) a pH-dependent enteric-coatingpolymer, (ii) a pH-independently water swelling polymer, and (iii) apore-forming component, wherein the extended release pellet has a closeto zero order in vitro release characteristic at acidic pH values up topH 6.8, an accelerated release above pH 6.8, and a more acceleratedrelease above pH 7.3.
 30. The extended release pellet according to claim29, wherein the pore-forming component is hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyvinylpyrrolidone, or polyethyleneglycol.
 31. An extended release pellet comprising pramipexole or apharmaceutically acceptable salt thereof prepared by wet or meltextrusion or melt granulation using excipients achieving extendedrelease without a further diffusion membrane.
 32. A method ofmanufacturing extended release pellets, the method comprising the stepsof: (1) providing an inert starter pellet core; (2) applying a solutionor dispersion of a first coating composition comprising pramipexole or apharmaceutically acceptable salt thereof, at least a binder, andoptionally excipient(s) onto the inert starter pellet core, wherein thepramipexole or a pharmaceutically acceptable salt thereof is used asunmilled material dissolved/dispersed in a solvent together with thebinder(s) and optional excipient(s), and subsequently drying the firstcoated pellet; (3) applying a solution or dispersion of a second coatingcomposition as functional coating composition onto the first coatedpellet obtained in step (2), wherein the coating composition comprises(a) at least one water-insoluble polymer and optionally a pore former or(b) a mixture of a pH-dependent enteric-coating polymer and apH-independently water swelling polymer, and optional excipient(s), anda solvent, and subsequently drying the obtained extended release pellet.33. The method according to claim 32, further comprising performingmanual screening after step (2) and/or step (3) in order to removeagglomerates.
 34. The method according to claim 32, wherein the applyingthe first coating composition of step (2) is done by spraying thesolution or dispersion of the first coating composition onto the inertstarter pellet core.
 35. The method according to claim 32, wherein theapplying the second coating composition of step (3) is done by sprayingthe solution or dispersion of the second coating composition onto thefirst coated pellet.
 36. A capsule containing extended release pelletsaccording to claim
 1. 37. A capsule containing extended release pelletsaccording to claim
 16. 38. The capsule according to claim 36, whereinthe capsule contains an amount of extended release pellets sufficient toprovide an effective daily dose of pramipexole or a pharmaceuticallyacceptable salt thereof.
 39. The capsule according to claim 37, whereinthe capsule contains an amount of extended release pellets sufficient toprovide an effective daily dose of pramipexole or a pharmaceuticallyacceptable salt thereof.